The design-by-adaptation approach to universal access: learning from videogame technology

This paper proposes an alternative approach to the design of universally accessible interfaces to that provided by formal design frameworks applied ab initio to the development of new software. This approach, design-byadaptation, involves the transfer of interface technology and/or design principles from one application domain to another, in situations where the recipient domain is similar to the host domain in terms of modelled systems, tasks and users. Using the example of interaction in 3D virtual environments, the paper explores how principles underlying the design of videogame interfaces may be applied to a broad family of visualization and analysis software which handles geographical data (virtual geographic environments, or VGEs). One of the motivations behind the current study is that VGE technology lags some way behind videogame technology in the modelling of 3D environments, and has a less-developed track record in providing the variety of interaction methods needed to undertake varied tasks in 3D virtual worlds by users with varied levels of experience. The current analysis extracted a set of interaction principles from videogames which were used to devise a set of 3D task interfaces that have been implemented in a prototype VGE for formal evaluation

The impact of the implementation of work hour requirements on residents' career satisfaction, attitudes and emotions

BACKGROUND: To assess the impact of work hours' limitations required by the Accreditation Council for Graduate Medical Education (ACGME) on residents' career satisfaction, emotions and attitudes. METHODS: A validated survey instrument was used to assess residents' levels of career satisfaction, emotions and attitudes before and after the ACGME duty hour requirements were implemented. The "pre" implementation survey was distributed in December 2002 and the "post" implementation one in December 2004. Only the latter included work-hour related questions. RESULTS: The response rates were 56% for the 2002 and 72% for the 2004 surveys respectively. Although career satisfaction remained unchanged, numerous changes occurred in both emotions and attitudes. Compared to those residents who did not violate work-hour requirements, those who did were significantly more negative in attitudes and emotions. CONCLUSION: With the implementation of the ACGME work hour limitations, the training experience became more negative for those residents who violated the work hour limits and had a small positive impact on those who did not violate them. Graduate medical education leaders must innovate to make the experiences for selected residents improved and still maintain compliance with the work hour requirements

Changes in the flexion relaxation response induced by lumbar muscle fatigue

<p>Abstract</p> <p>Background</p> <p>The flexion relaxation phenomenon (FRP) is an interesting model to study the modulation of lumbar stability. Previous investigations have explored the effect of load, angular velocity and posture on this particular response. However, the influence of muscular fatigue on FRP parameters has not been thoroughly examined. The objective of the study is to identify the effect of erector spinae (ES) muscle fatigue and spine loading on myoelectric silence onset and cessation in healthy individuals during a flexion-extension task.</p> <p>Methods</p> <p>Twenty healthy subjects participated in this study and performed blocks of 3 complete trunk flexions under 4 different experimental conditions: no fatigue/no load (1), no fatigue/load (2), fatigue/no load(3), and fatigue/load (4). Fatigue was induced according to the Sorenson protocol, and electromyographic (EMG) power spectral analysis confirmed that muscular fatigue was adequate in each subject. Trunk and pelvis angles and surface EMG of the ES L2 and L5 were recorded during a flexion-extension task. Trunk flexion angle corresponding to the onset and cessation of myoelectric silence was then compared across the different experimental conditions using 2 × 2 repeated-measures ANOVA.</p> <p>Results</p> <p>Onset of myoelectric silence during the flexion motion appeared earlier after the fatigue task. Additionally, the cessation of myoelectric silence was observed later during the extension after the fatigue task. Statistical analysis also yielded a main effect of load, indicating a persistence of ES myoelectric activity in flexion during the load condition.</p> <p>Conclusion</p> <p>The results of this study suggest that the presence of fatigue of the ES muscles modifies the FRP. Superficial back muscle fatigue seems to induce a shift in load-sharing towards passive stabilizing structures. The loss of muscle contribution together with or without laxity in the viscoelastic tissues may have a substantial impact on post fatigue stability.</p

The Impact of the Human DNA Topoisomerase II C-Terminal Domain on Activity

Type II DNA topoisomerases (topos) are essential enzymes needed for the resolution of topological problems that occur during DNA metabolic processes. Topos carry out an ATP-dependent strand passage reaction whereby one double helix is passed through a transient break in another. Humans have two topoII isoforms, alpha and beta, which while enzymatically similar are differentially expressed and regulated, and are thought to have different cellular roles. The C-terminal domain (CTD) of the enzyme has the most diversity, and has been implicated in regulation. We sought to investigate the impact of the CTD domain on activity.We have investigated the role of the human topoII C-terminal domain by creating constructs encoding C-terminally truncated recombinant topoIIalpha and beta and topoIIalpha+beta-tail and topoIIbeta+alpha-tail chimeric proteins. We then investigated function in vivo in a yeast system, and in vitro in activity assays. We find that the C-terminal domain of human topoII isoforms is needed for in vivo function of the enzyme, but not needed for cleavage activity. C-terminally truncated enzymes had similar strand passage activity to full length enzymes, but the presence of the opposite C-terminal domain had a large effect, with the topoIIalpha-CTD increasing activity, and the topoIIbeta-CTD decreasing activity.In vivo complementation data show that the topoIIalpha C-terminal domain is needed for growth, but the topoIIbeta isoform is able to support low levels of growth without a C-terminal domain. This may indicate that topoIIbeta has an additional localisation signal. In vitro data suggest that, while the lack of any C-terminal domain has little effect on activity, the presence of either the topoIIalpha or beta C-terminal domain can affect strand passage activity. Data indicates that the topoIIbeta-CTD may be a negative regulator. This is the first report of in vitro data with chimeric human topoIIs

Understanding recovery in the context of lived experience of personality disorders: a collaborative, qualitative research study

Background Concepts of recovery increasingly inform the development and delivery of mental health services internationally. In the UK recent policy advocates the application of recovery concepts to the treatment of personality disorders. However diagnosis and understanding of personality disorders remains contested, challenging any assumption that mainstream recovery thinking can be directly translated into personality disorders services. Methods In a qualitative interview-based study understandings of recovery were explored in extended, in-depth interviews with six people purposively sampled from a specialist personality disorders’ service in the UK. An interpretive, collaborative approach to research was adopted in which university-, clinical- and service user (consumer) researchers were jointly involved in carrying out interviews and analysing interview data. Results Findings suggested that recovery cannot be conceptualised separately from an understanding of the lived experience of personality disorders. This experience was characterised by a complexity of ambiguous, interrelating and conflicting feelings, thoughts and actions as individuals tried to cope with tensions between internally and externally experienced worlds. Our analysis was suggestive of a process of recovering or, for some, discovering a sense of self that can safely coexist in both worlds. Conclusions We conclude that key facilitators of recovery – positive personal relationships and wider social interaction – are also where the core vulnerabilities of individuals with lived experience of personaility disorders can lie. There is a role for personality disorders services in providing a safe space in which to develop positive relationships. Through discursive practice within the research team understandings of recovery were co-produced that responded to the lived experience of personality disorders and were of applied relevance to practitioners

NYESO-1/LAGE-1s and PRAME Are Targets for Antigen Specific T Cells in Chondrosarcoma following Treatment with 5-Aza-2-Deoxycitabine

Chondrosarcoma has no proven systemic option in the metastatic setting. The development of a non-cross-resistant strategy, such as cellular immunotherapy using antigen-specific T cells would be highly desirable. NY-ESO-1 and PRAME are members of the Cancer Testis Antigen (CTA) family that have been identified as promising targets for T cell therapy. LAGE-1 is a cancer testis antigen 90% homologous to NY-ESO-1, sharing the 157-165 A*0201 NY-ESO-1 epitope with its transcript variant, LAGE-1s. A number of CTA's have been induced using 5-Aza-2-Deoxycitabine (5-Aza-dC) in other cancers. We sought to evaluate the feasibility of targeting chondrosarcoma tumors using NY-ESO-1/LAGE-1s and PRAME specific T cells using 5-Aza-dC to induce antigen expression.We used 11 flash frozen tumors from the University of Washington tumor bank to test for the expression of NY-ESO-1, PRAME, LAGE-1s and LAGE-1L in chondrosarcoma tumors. Using four chondrosarcoma cell lines we tested the expression of these CTA's with and without 5-Aza-dC treatments. Finally, using NY-ESO-1/LAGE-1s and PRAME specific effectors that we generated from sarcoma patients, we evaluated the ability of these T cells to lyse A*0201 expressing chondrosarcoma cell lines in vitro both with and without 5-Aza-dC treatment.A minority (36%) of chondrosarcoma tumors expressed either NY-ESO-1 or LAGE-1s at >10% of our reference value and none expressed PRAME at that level. However, in all four of the chondrosarcoma cell lines tested, NY-ESO-1 and PRAME expression could be induced following treatment with 5-Aza-dC including in cell lines where expression was absent or barely detectable. Furthermore, NY-ESO-1/LAGE-1s and PRAME specific CD8+ effector T cells were able to specifically recognize and lyse A*0201 expressing chondrosarcoma cell lines following 5-Aza-dC treatment.These data suggest that adoptive immunotherapy in combination with 5-Aza-dC may be a potential strategy to treat unresectable or metastatic chondrosarcoma patients where no proven systemic therapies exist

Common Sole Larvae Survive High Levels of Pile-Driving Sound in Controlled Exposure Experiments

In view of the rapid extension of offshore wind farms, there is an urgent need to improve our knowledge on possible adverse effects of underwater sound generated by pile-driving. Mortality and injuries have been observed in fish exposed to loud impulse sounds, but knowledge on the sound levels at which (sub-)lethal effects occur is limited for juvenile and adult fish, and virtually non-existent for fish eggs and larvae. A device was developed in which fish larvae can be exposed to underwater sound. It consists of a rigid-walled cylindrical chamber driven by an electro-dynamical sound projector. Samples of up to 100 larvae can be exposed simultaneously to a homogeneously distributed sound pressure and particle velocity field. Recorded pile-driving sounds could be reproduced accurately in the frequency range between 50 and 1000 Hz, at zero to peak pressure levels up to 210 dB re 1µPa2 (zero to peak pressures up to 32 kPa) and single pulse sound exposure levels up to 186 dB re 1µPa2s. The device was used to examine lethal effects of sound exposure in common sole (Solea solea) larvae. Different developmental stages were exposed to various levels and durations of pile-driving sound. The highest cumulative sound exposure level applied was 206 dB re 1µPa2s, which corresponds to 100 strikes at a distance of 100 m from a typical North Sea pile-driving site. The results showed no statistically significant differences in mortality between exposure and control groups at sound exposure levels which were well above the US interim criteria for non-auditory tissue damage in fish. Although our findings cannot be extrapolated to fish larvae in general, as interspecific differences in vulnerability to sound exposure may occur, they do indicate that previous assumptions and criteria may need to be revised

H2AX phosphorylation at the sites of DNA double-strand breaks in cultivated mammalian cells and tissues

A sequence variant of histone H2A called H2AX is one of the key components of chromatin involved in DNA damage response induced by different genotoxic stresses. Phosphorylated H2AX (γH2AX) is rapidly concentrated in chromatin domains around DNA double-strand breaks (DSBs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress. γH2AX foci could be easily detected in cell nuclei using immunofluorescence microscopy that allows to use γH2AX as a quantitative marker of DSBs in various applications. H2AX is phosphorylated in situ by ATM, ATR, and DNA-PK kinases that have distinct roles in different pathways of DSB repair. The γH2AX serves as a docking site for the accumulation of DNA repair proteins, and after rejoining of DSBs, it is released from chromatin. The molecular mechanism of γH2AX dephosphorylation is not clear. It is complicated and requires the activity of different proteins including phosphatases and chromatin-remodeling complexes. In this review, we summarize recently published data concerning the mechanisms and kinetics of γH2AX loss in normal cells and tissues as well as in those deficient in ATM, DNA-PK, and DSB repair proteins activity. The results of the latest scientific research of the low-dose irradiation phenomenon are presented including the bystander effect and the adaptive response estimated by γH2AX detection in cells and tissues

Dual modification of Alzheimer’s disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach

In sporadic Alzheimer’s disease (AD), neurofibrillary lesion formation is preceded by extensive post-translational modification of the microtubule associated protein tau. To identify the modification signature associated with tau lesion formation at single amino acid resolution, immunopurified paired helical filaments were isolated from AD brain and subjected to nanoflow liquid chromatography–tandem mass spectrometry analysis. The resulting spectra identified monomethylation of lysine residues as a new tau modification. The methyl-lysine was distributed among seven residues located in the projection and microtubule binding repeat regions of tau protein, with one site, K254, being a substrate for a competing lysine modification, ubiquitylation. To characterize methyl lysine content in intact tissue, hippocampal sections prepared from post mortem late-stage AD cases were subjected to double-label confocal fluorescence microscopy using anti-tau and anti-methyl lysine antibodies. Anti-methyl lysine immunoreactivity colocalized with 78 ± 13% of neurofibrillary tangles in these specimens. Together these data provide the first evidence that tau in neurofibrillary lesions is post-translationally modified by lysine methylation